Involvement of heregulin-β2 in the acquisition of the hormone- independent phenotype of breast cancer cells

Careen K. Tang, Cynthia Perez, Thomas Grunt, Caroline Waibel, Cheryl Cho, Ruth Lupu

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

The erbB-2 receptor plays an important role in the prognosis of breast cancer. Amplification or overexpression of the erbB-2 proto-oncogene has been detected in 30% of breast cancers and is associated with poor patient prognosis. The significance of erbB-3 and erbB-4 in breast cancer is not yet known. The discovery of the growth factor heregulin (HRG) has allowed us to investigate a number of biological events that are regulated by erbB-2, -3, and -4 signal transduction. To determine the role of HRG in breast cancer tumor progression, we have developed an in vitro/in vivo model. We transfected HRG cDNA into the estrogen receptor (ER)positive breast cancer cell line, MCF-7, and studied these cells as they progressed from a hormone- dependent to -independent phenotype. The biochemical and biological characteristics presented here demonstrate that overexpression of HRG induces morphological changes in MCF-7 cells as well as erbB-2, erbB-3, and erbB-4 autophosphorylation. MCF-7/heregulin-transfected cells, which express relatively high levels of HRG, developed estrogen independence and resistance to antiestrogens in vitro and in vivo. This is consistent with a more aggressive hormone-independent phenotype. In contrast with control parental/wild-type cells, estradiol-mediated down regulation of erbB-2 expression is blocked completely in this particular model system. These results indicate that HRG plays a role in the disruption of ER function. When a transient transfection with an ERE-CAT construct was introduced into these HRG-transfected MCF-7 cells, we observed that the ER was transcriptionally inactive. This suggests that ER signaling is altered in HRG-transfected cells. We observed that overexpression of HRG induces a more aggressive, hormone-independent phenotype that is most likely directly related to the constitutive activation of the erbB-2, erbB-3, and erbB-4 receptor signaling cascade. The data presented here suggest a close cross-regulation between the erbB-2/4 receptors and ER and provide new insights into the mechanism by which breast cancer cells acquire a hormone-independent phenotype.

Original languageEnglish (US)
Pages (from-to)3350-3358
Number of pages9
JournalCancer Research
Volume56
Issue number14
StatePublished - Jul 15 1996
Externally publishedYes

Fingerprint

Neuregulin-1
Hormones
Breast Neoplasms
Phenotype
Estrogen Receptors
MCF-7 Cells
ErbB-2 Receptor
Estrogen Receptor Modulators
Proto-Oncogenes
Transfection
Estradiol
Signal Transduction
Intercellular Signaling Peptides and Proteins
Estrogens
Down-Regulation
Complementary DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Involvement of heregulin-β2 in the acquisition of the hormone- independent phenotype of breast cancer cells. / Tang, Careen K.; Perez, Cynthia; Grunt, Thomas; Waibel, Caroline; Cho, Cheryl; Lupu, Ruth.

In: Cancer Research, Vol. 56, No. 14, 15.07.1996, p. 3350-3358.

Research output: Contribution to journalArticle

Tang, CK, Perez, C, Grunt, T, Waibel, C, Cho, C & Lupu, R 1996, 'Involvement of heregulin-β2 in the acquisition of the hormone- independent phenotype of breast cancer cells', Cancer Research, vol. 56, no. 14, pp. 3350-3358.
Tang, Careen K. ; Perez, Cynthia ; Grunt, Thomas ; Waibel, Caroline ; Cho, Cheryl ; Lupu, Ruth. / Involvement of heregulin-β2 in the acquisition of the hormone- independent phenotype of breast cancer cells. In: Cancer Research. 1996 ; Vol. 56, No. 14. pp. 3350-3358.
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